Mass transfer devices used in the medical field typically utilize a microporous membrane as a substitute for the natural function of an organ or tissue of a human body. For example, a microporous membrane oxygenator provides a substitute for a patient's lung functions. While the present invention may be applied to a variety of different microporous membrane mass transfer devices, the preferred embodiment of the present invention is described below with respect to microporous membrane oxygenators.
Microporous membranes are typically formed from a hydrophobic material such as polypropylene and include micropore structures of a size significantly smaller than blood cells. Microporous membrane oxygenators thus allow gas to be exchanged across the membrane while preventing significant infiltration or wetting of the membrane pores by a patient's blood plasma over the course of a cardiopulmonary bypass procedure.
The manufacture of both flat sheet and hollow fiber microporous membrane oxygenators requires a relatively complex process which includes cutting the fragile microporous membrane material and sealing or "potting" that material within a housing to form opposing fluid-containing (i.e., blood and gas) compartments separated by the microporous membrane. Additionally, due to the critical medical applications for which microporous membrane oxygenators are used, each completed oxygenator must be tested to verify the integrity of the microporous membrane material and the seals within the housing to ensure that the gas and the blood can not leak between the two separate compartments. Such leak testing is an integral part of the manufacturing process for any microporous membrane mass transfer device such as microporous membrane oxygenators.
Previous methods for testing the integrity of microporous membranes used within oxygenators typically require charging one side of the microporous membrane (e.g., the "blood compartment" of a membrane oxygenator) with pressurized water and then visually observing the other side of the microporous membrane (e.g., the "gas compartment" of a membrane oxygenator) for water leaking across or around the membrane. If no visual evidence of water or water vapor is observed within a predetermined time interval (e.g., five minutes for a hollow fiber oxygenator or fifteen minutes for a flat sheet oxygenator), the leak-test is concluded and the oxygenator is passed on to a final sterilization process prior to shipping. However, if water is detected on the opposite side of the microporous membrane during the course of the test, the microporous membrane is considered defective and the entire oxygenator is discarded.
The above-described visual leak testing method suffers from several disadvantages. First, the leak test is relatively slow in that it requires 5-15 minutes to complete, after which the microporous membrane must be allowed to dry completely. Drying typically requires a relatively longer period of time (e.g., an additional 10-12 minutes for a hollow fiber oxygenator and an additional 90 minutes for a flat sheet oxygenator). Thus, the total time required for testing and drying a flat sheet microporous membrane utilizing the prior-art leak test is approximately 105 minutes, during which time the newly manufactured mass transfer device must remain within the manufacturing clean room. This represents a significant manufacturing cost, particularly in light of the cost of clean room facilities.
A second disadvantage is that the prior art leak-test method is labor intensive due to its reliance on trained technicians to visually detect leaks within the microporous membrane device. Additionally, due to the production-line nature of the manufacturing process, it is possible that even a trained technician will fail to notice small leaks in some membranes (i.e., a "false negative" result). On the other hand, it is also possible for technicians to incorrectly conclude that condensation which forms in the gas compartment of the oxygenator is the result of a water leak through a defective membrane (i.e., a "false positive" result). However, such condensation is not uncommon when warm air is used to blow the water out of the blood side of the oxygenator and dry the membrane (i.e., the warm air may cause water vapor to pass through the microporous membrane where it cools and condenses in the gas side of the oxygenator). Furthermore, this visual leak test provides little or no capability to detect weakened or compromised microporous membranes which nevertheless retain enough integrity to avoid passing fluid during the course of the test, but which have an elevated risk of failure during the typical prolonged period of use involved in a medical procedure such as cardiopulmonary bypass.
Improvements in the accuracy of such visual leak tests have been attempted by employing an electrical circuit to automate the testing process. For example, it is well known in the art of rubber glove testing that the a glove may be filled with water and dipped in an electrolyte bath to which a voltage has been applied. If an electrode placed within the glove detects current flowing through the circuit completed by the electrolyte bath on the exterior of the glove, a defect (such as a tear or a pinhole) is indicated and the glove is discarded. A related method used for testing the integrity of microporous membranes is described in U.S. Pat. No. 5,477,155, issued Dec. 19, 1995, for a CURRENT FLOW INTEGRITY TEST ("the '155 Patent"). In brief, the '155 Patent discloses a process for verifying the integrity of and for analyzing the pore-size distribution of porous membranes and membrane filters. The '155 Patent describes contacting both sides of the porous membrane with a liquid and applying an electrical potential across the membrane. The pressure on at least one side of the membrane is gradually increased and changes in electrical conductivity across the porous membrane are measured to determine a distribution of the different pore sizes within the porous membrane. In essence, the conductivity across the porous membrane rises as the pressure of the liquid rises and the pores of smaller size are intruded or wetted. Using this method, defects within the porous membrane (corresponding to pores of excessive size) can be detected before the pressure applied to the porous membrane exceeds a characteristic intrusion or wetting pressure which corresponds to the intrusion or wetting of the largest pores normally present within the porous membrane.
Regardless of whether a visual or electrical test is used to determine the integrity of a microporous membrane, once a membrane oxygenator has been successfully tested and dried, it is sometimes desirable to subject the oxygenator to additional manufacturing processing, such as the application of a biocompatible material to the membrane and other blood contact surfaces of the oxygenator. For example, U.S. Pat. No. 5,643,681, issued Jul. 1, 1997, for a BIOCOMPATIBLE COATED ARTICLE and assigned to the assignee hereof ("the '681 Patent"), describes a process for coating blood contact surfaces within oxygenators or similar mass transfer devices to improve the biocompatibility of the device relative to a similar uncoated device. In general, biocompatibility reduces the trauma or damage to components of the blood or other body fluids, such as blood cells, which will typically result from the contact of the blood or fluid with a non-natural surface. Specifically, the '681 Patent describes a process of coating an assembled and leak-tested oxygenator with a solvent containing a triblock copolymer known commercially as SMA-423 (see column 8, lines 29-61). The '681 Patent notes that several advantages arise from applying the biocompatible coating after oxygenator assembly (or at least after assembly of the separate components such as the oxygenation compartment and the heat exchanger) as opposed to using pre-coated membranes and heat exchangers. These advantages include reduced manufacturing costs and a reduction in the amount of wasted coating material since the coating is not applied to defective oxygenators such as those oxygenators which do not pass the leak test.
Thus, the membrane coating process described in the '681 Patent occurs only after a successful membrane leak test has been completed and further requires a separate cycle of filling the blood compartment of the membrane oxygenator with the biocompatible solvent and then allowing the membrane to dry completely. To ensure that the biocompatible coating is durably applied to the membrane so that the coating does not dissolve in contact with blood, the '681 Patent further describes an additional step of exposing the coated membrane to ionizing radiation which was found to tenaciously adhere the particular biocompatible coating to the surface of the membrane. Thus, while the '681 Patent describes a process for applying a biocompatible coating to a microporous membrane oxygenator, the process requires at least two additional post-assembly steps following the membrane leak test to both apply the coating and then ensure the adherence of the coating.
Aside from the application of biocompatible coatings, it is also known to apply surface active agents or "surfactants" to a microporous membrane oxygenator to enhance the wettability of the microporous membrane and thereby speed the priming or debubbling process required before the oxygenator can be used to treat a patient. An example of such a reference is U.S. Pat. No. 5,162,102, issued Nov. 10, 1992, for a MEDICAL INSTRUMENT AND PRODUCTION THEREOF ("the '102 Patent"). The '102 Patent describes a process of manufacturing a microporous membrane oxygenator in which a surfactant is deposited onto the membrane and other blood contact surfaces to speed air removal during a priming operation. The particular surfactant described in the '102 Patent (Pluronic F-68) is a solid surfactant which dissolves within the priming solution so that it may be distributed over all of the of the blood contact surfaces of the oxygenator as the priming solution is recirculated through the oxygenator. The '102 Patent further describes that the surfactant ensures efficient priming of the blood contact surfaces (including the microporous membrane) by increasing the wettability of those surfaces, thereby allowing the priming liquid to pass over the blood contact surfaces without leaving fine bubbles adhered to the surfaces.
The '102 Patent also describes a number of methods for depositing the solid surfactant onto the oxygenator blood contact surfaces, including blowing a surfactant powder against the blood contact surfaces and, alternatively, mixing the surfactant with the test liquid used during the membrane leak test and then drying the oxygenator after the test to remove the test liquid and leave the solid surfactant deposited on the membrane. However, when the F-68 surfactant is added to the test liquid during the leak test, the '102 Patent describes that the surfactant improves the wettability of the membrane and thereby increases the sensitivity of the leak test by allowing the test liquid on the blood side of the membrane to leak more easily through pinholes in the membrane (see column 9, lines 31-33 of the '102 Patent).
Regardless of whether the surfactant is applied as a powder or as a residue following a leak test, the '102 Patent only requires that the surfactant be deposited within the oxygenator housing so that it may ultimately mix with and dissolve within the priming solution to prevent adhesion of bubbles to the blood contact surfaces during priming (see column 7, lines 12-28 of the '102 Patent). Thus, the solid surfactant described within the '102 Patent beneficially enhances the wettability of the oxygenator blood contact surfaces to both improve the priming process and also increase the sensitivity and effectiveness of the membrane leak test (by increasing the wettability of the membrane to allow the test liquid to more easily pass through the membrane and indicate defects) when the surfactant is mixed with the test liquid. However, the surfactant of the '102 Patent does not appear to have any lasting effects following the priming process in which the surfactant is dissolved with the priming solution. Specifically, it does not appear that the disclosed surfactant (Pluronic F-68) remains adhered to the blood contact surfaces of the oxygenator following the priming process, nor is there any suggestion that the Pluronic surfactant could be applied as a coating to the blood contact surfaces to enhance the biocompatibility of those surfaces. Rather, the Pluronic surfactant is only disclosed as a wetting agent for removing air bubbles and increasing the sensitivity of the membrane leak test.
Thus, while the prior art describes processes for applying biocompatible coatings to microporous membrane oxygenators, these processes require additional steps which significantly increase the complication of the membrane oxygenator manufacturing process. Additionally, while other prior art processes provide for beneficially depositing surfactants onto blood contact surfaces of a microporous membrane oxygenator without adding additional steps to the manufacturing process (e.g., mixing the surfactant with the test liquid during the membrane leak test), these processes do not provide for the durable application of a surfactant to such blood contact surfaces, nor do they provide for enhancing the biocompatibility of those surfaces.
These and other considerations have contributed to the evolution of the present invention which is summarized below.